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DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency.

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journal contribution
posted on 2023-12-11, 12:01 authored by Cynthia Turnbull, Josiah Bones, Maurice Stanley, Arti Medhavy, Hao Wang, Ayla May D Lorenzo, Jean Cappello, Somasundhari Shanmuganandam, Abhimanu Pandey, Sandali Seneviratne, Grant J Brown, Xiangpeng Meng, David Fulcher, Gaetan Burgio, Si Ming Man, Carmen de Lucas Collantes, Mercedes Gasior, Eduardo López Granados, Pilar Martin, Simon H Jiang, Matthew C Cook, Julia I Ellyard, Vicki Athanasopoulos, Ben Corry, Pablo F Canete, Carola G Vinuesa
Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor-β. Consistent with DECTIN-1's Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.


Crick (Grant ID: CC2228, Grant title: Vinuesa CC2228)


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